Adenosine is known to be an endogenous modulator of a number of physiological functions and these are mediated by the interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins. Adenosine exerts effects in cardiovascular, central nervous, respiratory systems, kidney, adipose and platelets. Recent advances in molecular biolog) coupled with several pharmacological studies have lead to identification of at least four subtypes of adenosine receptors, A1, A2B, A2b and A3. The A1 and A3 receptors down-regulate cellular cAMP levels through their coupling to G protein, which inhibit adenylate cyclase. In contrast, A2A and A2B receptors couple to G protein that activate adenylate cyclase and increase intracellular levels of cAMP.
Advances in understanding the role of adenosine and its receptors in physiology and pathophysiology as well as new developments in medicinal chemistry of these receptors have identified potential therapeutic areas for drug development. With the combination of pharmacological data, using selective ligands and genetically modified mice, important progress has been made toward an understanding of the role of ARs in a variety of diseases, such as inflammatory conditions, sepsis, heart attack, ischemia-reperfusion injury, vascular injury, spinal cord injury, chronic obstructive pulmonary disease (COPD), asthma, diabetes, obesity, inflammatory bowel disease, retinopathy, and Parkinson's Disease (PD).
The A2B adenosine receptor subtype (see Fektistov, I., Biaggioni, I. Pharmacol. Rev. 1997, 49, 381-402) has been identified in a variety of human and murine tissues and is involved in the regulation of vascular tone, smooth muscle growth, angiogenesis, hepatic glucose production, bowel movement, intestinal secretion, and mast cell degranulation. A2B receptors have been implicated in mast cell activation and asthma, control of vascular tone, cardiac myocyte contractility, cell growth and gene expression, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (Pharmacological Reviews Vol. 49, No. 4).
A2B receptors modulate mast cell function. Adenosine activates adenylate cyclase and protein kinase C, and potentiates stimulated mediator release in mouse bone marrow derived mast cells. (TiPS—April 1998 (Vol. 19)). Activation of A2B receptors in HMC-1 augments IL-8 release and potentiates PMA-induced secretion of IL-8. Thus, adenosine would contribute to the asthmatic response by acting on the mast cell to enhance the release of proinflammatory mediators. (Pulmonary Pharmacology & Therapeutics 1999, 12, 111-114). In COPD, transformation of pulmonary fibroblasts into myofibroblasts is considered a major mechanism. Activation of the A2B AR is involved in this process. Selective A2B antagonists are expected to have beneficial effect on pulmonary fibrosis (Curr. Drug Targets, 2006, 7, 699-706; Am. J. Resper. Cell. Mol. Biol., 2005, 32, 228). A2B antagonists can be used as wound healing agents. Activation of the A2B AR promotes angiogenesis by increasing the release of angiogenic factors and A2B antagonists are useful to block angiogenesis (Circ. Res., 2002, 90, 531-538). A2B AR may be involved in the inhibition cardiac fibroblast (CF) proliferation (Am. J. Physiol. Heart Circ. Physiol., 2004, 287, H2478-H2486). Adenosine stimulates Cl-secretion in the intestinal epithelia pointing towards a possible treatment for cystic fibrosis patients with CFTR mutation (Am. J. Respir. Cell Mol. Biol., 2008, 39, 190-197). High affinity A2B antagonists are effective in hot plate model suggestive of the role of A2B in nociception and can be used as potential analgesic agents (The J. of Pharmacol. and Exp. Ther., 2004, 308, 358-366).
A2B receptor is involved in release of IL-6. Increasing evidence suggests that IL-6 plays a role in Alzheimer's disease in the context of inflammatory process associated with disease. Hence A2B receptor antagonist might be useful for Alzheimer's disease. The A2B ARs are involved in the stimulation of nitric oxide production during Na+-linked glucose or glutamine absorption. They are involved in glucose production in hepatocytes upon agonist stimulation. A2B-receptor antagonists showed an anti-diabetic potential mainly by increasing plasma insulin levels under conditions when the adenosine tonus was elevated in-vivo and increased insulin release in-vitro (J. Pharm. Pharmacol. 2006 December; 58(12):1639-45). Thus A2B antagonists may serve as a novel target for the treatment of this metabolic disease.
It has been demonstrated that adenosine activation of the A2B adenosine receptor increase cAMP accumulation, cell proliferation and VEGF expression in human retinal endothelial cells. Activation of A2BAdoR increased vascular endothelial cell growth factor mRNA and protein expression in human retinal endothelial cells. Adenosine also has a synergistic effect with VEGF on retinal endothelial cell proliferation and capillary morphogenesis in vitro. Such activity is necessary in healing wounds, but the hyperproliferation of endothelial cells promotes diabetic retinopathy. Also, an undesirable increase in blood vessels occurs in neoplasia. Accordingly, inhibition of binding of adenosine to A2B receptors in the endothelium will alleviate or prevent hypervasculation, thus preventing retinopathy and inhibiting tumor formation.
In view of the physiological effects mediated by adenosine receptor, several A2B receptor antagonists have been recently disclosed for the treatment or prevention of asthma, bronchoconstriction, allergic diseases, hypertension, atherosclerosis, reperfusion injury, myocardial ischemia, retinopathy, inflammation, gastrointestinal tract disorders, cell proliferation diseases and/or diabetes mellitus. See for example W02008002902, W02007149277, W02007017096, W02007109547, W02006091896, W02006015357, W02005042534, W02005021548, W02004106337, W02003000694, W02003082873, W02003006465, W02003053361, W02003002566, W02003063800, W02003042214, W02003035639, EP1283056, W0200073307, W0200125210 , W02000073307, US20050119287, US20060281927.
Recent findings in Nature Medicine, 2011 suggests elevated levels of adenosine and 2,3-DPG in the blood of Sickle Cell Disease (SCD) transgenic mice at steady state. These findings led to the discovery that elevated adenosine signaling through A2BR promotes sickling by inducing 2,3-DPG production. Lowering adenosine concentrations or interfering with activation of A2BR reduced sickling, hemolysis and tissue injury in SCD transgenic mice both at steady state and during an acute crisis event. Both adenosine and 2,3-DPG concentrations were elevated in the blood of individuals with SCD, and it was shown that adenosine signaling through the A2BR increases 2,3-DPG concentrations and induces sickling of RBCs derived from humans with SCD. These findings provide evidence for the pathogenic consequences of excessive adenosine signaling in SCD and suggest that interfering with adenosine signaling (particularly with A2BR activation on erythrocytes) may be an effective mechanism-based therapy for preventing sickling and hemolysis in individuals with SCD and ultimately for reducing the life-threatening complications associated with SCD. Thus A2B antagonists may serve as a novel target for the treatment of SCD.
Indian patent application No. 571/CHE/2009 discloses A2B adenosine receptor antagonists that are potent and selective for the A2B adenosine receptor. Such compounds are known to be relatively insoluble in aqueous media and difficult to formulate at higher doses using conventional pharmaceutical excipients. It has been surprisingly found that the compounds of the present disclosure which are more soluble in aqueous media and/or conventional pharmaceutical excipients are active prodrugs of the compounds disclosed in 571/CHE/2009. The compounds of the present disclosure, thereby make it possible to formulate at higher doses in a manner that provides sufficient plasma levels of the compound for development.